Effects of dietary intervention on diabetic nephropathy: an umbrella review of systematic reviews and meta-analyses of randomized controlled trials

Objective To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary intervention and diabetic nephropathy (DN). Methods We conducted an umbrella review of existing meta-analyses of randomized controlled trials (RCTs) that focused on the effects of dietary intervention on DN incidence. The literature was searched via PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. According to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), evidence of each outcome was evaluated and graded as “high”, “moderate”, “low” or “very low” quality to draw conclusions. Additionally, we classified evidence of outcomes into 4 categories. Results We identified 36 meta-analyses of RCTs and 55 clinical outcomes of DN from 395 unique articles. Moderate-quality evidence suggested that probiotic supplementation could significantly improve blood urea nitrogen (BUN), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in DN patients. Low-quality evidence indicated that probiotic supplementation significantly improved the serum creatinine concentration, urinary albumin–creatinine ratio (UACR), fasting blood glucose (FBG), HbA1c and high-density lipoprotein cholesterol (HDL-C) in DN patients. In addition, low-quality evidence suggested that a salt restriction diet could significantly improve the creatinine clearance rate (CrCl) in patients with DN. Low-quality evidence suggested that vitamin D supplementation could significantly improve the UACR in patients with DN. In addition, low-quality evidence has indicated that soy isoflavone supplementation could significantly improve BUN, FBG, total cholesterol (TC), triglyceride (TG) and LDL-C levels in patients with DN. Furthermore, low-quality evidence suggested that coenzyme Q10 supplementation could significantly improve HbA1c, TC and HDL-C in patients with DN, and dietary polyphenols also significantly improved HbA1c in patients with DN. Finally, low-quality evidence suggested that supplementation with antioxidant vitamins could significantly improve the serum creatinine concentration, systolic blood pressure, and HbA1c level in patients with DN. Given the small sample size, all significantly associated outcomes were evaluated as class IV evidence. Conclusion Moderate to low amounts of evidence suggest that supplementation with probiotics, vitamin D, soy isoflavones, coenzyme Q10, dietary polyphenols, antioxidant vitamins, or salt-restricted diets may significantly improve clinical outcomes in patients with DN. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024512670.


Introduction
Diabetic nephropathy (DN), a common microvascular complication of diabetes, is an important cause of chronic kidney disease (CKD) and end-stage renal disease.Patients with DN often need dialysis to maintain life, and this condition has a high fatality rate (1).There are many risk factors affecting the occurrence and development of DN, among which the most important risk factors include family history, hypertension, dyslipidemia, obesity and insulin resistance; other risk factors include elevated HbA1c levels, elevated systolic blood pressure, proteinuria and smoking (2).Dietary intervention is an important means to control the progression of DN by reducing the risk factors for DN.The main goal of DN treatment is to prevent microalbuminuria from progressing to macroalbuminuria and ultimately to protect renal function.By controlling a healthy and balanced diet, DN patients can delay the progression of kidney damage and related secondary diseases, such as hypertension, hyperlipidemia, and uremia; in contrast, an unhealthy diet will burden kidney function.Therefore, maintaining a delicate balance between nutrient intake and physiological load is essential for maintaining patients' quality of life (3).
Effective diet management can not only help control DN but also improve the quality of life of patients (2,3).According to the current literature, dietary interventions such as probiotic supplementation, a low-salt diet, soy isoflavone supplementation, vitamin supplementation and coenzyme Q10 supplementation can effectively improve the clinical outcome of DN patients, delay the progression of DN, and improve their quality of life (4)(5)(6)(7)(8)(9)(10)(11).
Although numerous meta-analyses of randomized controlled trials (RCTs) have evaluated a range of effects of dietary intervention on DN incidence in recent years, drawbacks in terms of the research design, differences in assessments of exposure factors, and inconsistent outcomes have made it difficult to draw definitive conclusions .Before developing effective dietary management strategies for DN, it is necessary to systematically evaluate the quality of the methodology, potential biases, and validity of all studies available for the effects of dietary intervention on DN.Therefore, we conducted an umbrella review of the meta-analyses to provide an overview of the evidence on the effects of dietary intervention on DN.

Design and registration
We systematically searched, extracted, and analyzed the data from reported systematic reviews and meta-analyses that focused on the effects of dietary intervention on DN according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (40).The present umbrella review adhered to the methodological guidance outlined in the Joanna Briggs Institute Manual for Evidence Synthesis of Umbrella Reviews (41) and followed the procedures delineated in the Cochrane Handbook for Conducting Systematic Reviews (42).Furthermore, we proactively enrolled our umbrella review in the International Prospective Register of Systematic Reviews (PROSPERO), with the registration number CRD42024512670.(https://www.crd.york.ac.uk/PROSPERO/).

Eligibility criteria
Systematic reviews and meta-analyses of RCTs evaluating the effects of dietary intervention on DN incidence in individuals of any ethnicity or sex in all countries and settings were eligible for inclusion.Data on individual dietary interventions were extracted separately if two or more dietary interventions were reported in a single meta-analysis.If two or more meta-analyses (those published more than 24 months apart) were performed on the same dietary intervention and clinical outcome of DN, we included the latest meta-analysis for data analysis.In the event that multiple metaanalyses were conducted within a 24-month timeframe, preference was given to the meta-analysis encompassing the highest number of RCTs.If an equal number of RCTs existed, priority was assigned to the meta-analysis with a superior AMSTAR score.In addition, if the latest meta-analysis did not perform dose-response analysis, while another meta-analysis did, both studies were included for data extraction.Non-English studies and animal and cell culture studies were also excluded.

Population
This umbrella review is centered on systematically reviewing meta-analyses that assess the effects of dietary intervention on DN.The primary focus of the original articles incorporated within these systematic reviews and meta-analyses should be directed toward identifying dietary interventions that have the potential to either improve or exacerbate the clinical outcomes of DN.Studies evaluating the efficacy of a certain dietary intervention for the risk of DN were excluded.

Exposure
We included a meta-analysis that reported at least 1 type of dietary intervention for DN, including probiotics, a salt restriction diet, vitamin D, soy isoflavone, and low-protein diets.The efficacy of dietary intervention on the clinical outcomes of DN was evaluated by the risk ratio (RR), mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs).

Study designs
Only systematic reviews and meta-analyses of RCTs evaluating the effects of dietary intervention on DN incidence in individuals of any ethnicity or sex in all countries and settings were eligible for inclusion.All the included systematic reviews and meta-analyses needed to focus on dietary intervention in DN patients and describe the meta-analysis methods in detail, including the complete search strategy, inclusion and exclusion criteria, literature quality evaluation criteria, result evaluation methods, analysis methods and procedures, and interpretation criteria.

Information sources
In our study, we systematically searched PubMed, Embase, the Web of Science, and the Cochrane Database of Systematic Reviews until July 2023 for relevant systematic reviews and meta-analyses of RCTs.We also reviewed the reference lists of the included metaanalyses to find additional relevant articles.

Study selection
All the retrieved literature was screened using Endnote X9.After excluding duplicates, two authors screened the titles and abstracts and identified meta-analyses that met the inclusion criteria through full-text reading independently.All disagreements between the two authors were resolved by a third author.In addition, we hand-searched studies from the reference lists to identify meta-analyses that might have been excluded (Figure 1).

Assessment of methodological quality
The methodological quality of each meta-analysis was assessed by two authors using AMSTAR, a validated, stringent, and reliable tool for evaluating systematic reviews and meta-analyses (44,45).In addition, according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), evidence of each health outcome was evaluated and graded as "high", "moderate", "low" or "very low" quality to draw conclusions (46).Additionally, we classified the evidence of outcomes into 4 categories following the evidence classification criteria: class I (convincing evidence), class II (highly suggestive evidence), class III (suggestive evidence), class IV (weak evidence) and NS (nonsignificant) (47-50).The detailed criteria for evidence classification are shown in Table 1.

Data extraction
Two investigators autonomously retrieved the pertinent data from each qualifying study: 1) name of the author, 2) publication date, 3) dietary intervention, 4) control, 5) outcomes, 6) number of included studies, 7) sample size, 8) length of follow-up, and 9) MD or SMD estimates with 95% CIs.In addition, we extracted the meta-analytic model used (random or fixed), estimate of heterogeneity (I 2 and Cochran's Q test) and small-study assessment (Egger's test, Begg's test and funnel plot).When dose response analysis and subgroup analysis were performed, we extracted the P value for nonlinearity and any reported estimate for subgroup analysis.Any disagreements were resolved by a third author.

Data summary
We recalculated the RR, MD or SMD with 95% CIs through random or fixed effects models and evaluated the heterogeneity (I 2 and Cochran's Q test) and small-study effects (Egger or Begg test for each systematic review and meta-analysis with more than 10 studies) in each meta-analysis when sufficient data were provided (51-53).For dietary interventions identified as class I-II evidence, high-quality evidence or moderate-quality evidence, we conducted sensitivity analysis when sufficient data were available to determine the effect of some individual studies on the total significance of the evidence.Dose-response analysis of DN incidence associated with any dietary intervention was also performed.Furthermore, if the most recent meta-analysis did not involve clinical studies that involved other meta-analyses, we combined the data of these studies and performed a reanalysis.A P < 0.10 was considered to indicate heterogeneity, and for other tests, P < 0.05 was considered to indicate statistical significance.Review Manager v5.4.1 (Cochrane Collaboration, Oxford, UK) was used for evidence synthesis.Egger and Begg tests, along with sensitivity analysis, were performed using Stata v15.1.

Characteristics of the meta-analyses
A flowchart of the literature search and selection process is presented in Figure 1.After a systematic literature search, 501 unique articles were identified.A total of 36 meta-analyses were yielded based on our inclusion criteria.We extracted 9 unique dietary interventions (including probiotics, a salt restriction diet, vitamin D, soy isoflavone, CoQ10, ketoanalog, dietary polyphenols, antioxidant vitamins, and low-protein diets) and 55 corresponding outcomes in meta-analyses, including 34 significantly associated outcomes and 21 nonsignificantly associated outcomes (Table 2).After a careful evaluation of evidence quality using established criteria, all outcomes were classified as IV or NS (nonsignificant) evidence.In addition, according to the GRADE rating criteria, only five dietary interventions were rated as moderate-quality evidence, 33 were rated

Evidence class Description
Class I: convincing evidence >1000 cases (or >20,000 participants for continuous outcomes), statistical significance at P < 10 −6 (random-effects), no evidence of small-study effects and excess significance bias; 95% prediction interval excluded the null, no large heterogeneity (I 2 < 50%) Class II: highly suggestive evidence >1000 cases (or >20,000 participants for continuous outcomes), statistical significance at P < 10 −6 (random-effects) and largest study with 95% CI excluding the null value Class III: suggestive evidence >1000 cases (or >20,000 participants for continuous outcomes) and statistical significance at P < 0.001

Salt restriction diet
A total of 3 meta-analyses (10, 13, 30) studied the effect of a salt restriction diet on DN incidence.The meta-analysis of Hodson et al.

Heterogeneity
In our study, 74.5% of the outcomes were reanalyzed using a random or fixed effects model.The reanalysis revealed that approximately 36.6% of the examined outcomes exhibited significant heterogeneity (I 2 > 50% or Cochran's Q test P < 0.1).The heterogeneity of most of the outcomes could be attributed to various potential factors, such as study setting, geographical region, ethnicity, sex, age, study quality, sample size, follow-up duration, and adjustment for confounding variables.For the remaining 25.5% of the unanalyzed outcomes, approximately 50% exhibited significant heterogeneity.

Assessment of risk of bias
In our reanalysis, Egger's test assessed publication bias for 19.5% of the total outcomes, revealing publication bias in 1 of them.For nonreanalyzed outcomes, publication bias was detected in 35.7% of the outcomes via statistical tests or funnel plots.Importantly, other outcomes either showed no significant publication bias or lacked reported bias assessments.

AMSTAR score, GRADE and evidence classification
The median AMSTAR score for all outcomes was 8 (8-11), and further detailed AMSTAR scores specific to each outcome can be found in Supplementary Table S1.For the GRADE, five outcomes (change in BUN (probiotics), change in TC (probiotics), change in LDL-C (probiotics), change in HbA1c (vitamin D), change in LDL-C (CoQ10)) were downgraded to "moderate" quality given the imprecision, and the remaining outcomes were downgraded to "low" or "very low" due to the risk of bias, inconsistency, indirectness, or imprecision.Supplementary Table S2 shows the detailed GRADE classification for each outcome.In terms of evidence, all outcomes were classifi ed as IV or NS (nonsignificant) because of the small sample size.

Discussion Principal findings and possible explanations
Relevant studies have shown that the incidence of DN is increasing rapidly, and patients with DN accounted for 20% to 40% of type 2 diabetes patients in the community from 2009 to 2012 (54).It is not only the main cause of death in type 1 diabetes patients but also an important factor threatening the health of type 2 diabetes patients (55).At present, it is believed that the disease progression of DN is difficult to reverse, the risk factors involved in the progression of DN cannot be identified, and effective measures cannot be taken to delay the progression of disease to end-stage nephropathy (56).With the increase in the number of DN patients, the disease burden on society and families will also increase (57).In recent years, due to the deepening of basic research, the treatment of DN has taken a new direction.Several scholars have proposed that probiotics may improve and prevent metabolic diseases such as DN through changes in the human intestinal flora (58).In addition, some animal model studies have shown that soy foods can prevent kidney disease and delay the deterioration of kidney function (59,60).Giving soy foods instead of meat to DN patients can improve kidney function (61,62).Furthermore, a large number of animal and cellular experiments and clinical studies have shown that active vitamin D has a renoprotective effect and may play a role in inhibiting the inflammatory response, antioxidative stress, and renal fibrosis; inhibiting the renin-angiotensin system; and improving insulin resistance (4,22,24,28).
To date, a large number of researchers worldwide have carried out clinical research and evidence-based medical research on the effects of dietary intervention on DN.This umbrella evaluation evaluated the advantages and disadvantages of existing evidencebased medical methods from systematic reviews and meta-analyses on the effects of dietary intervention on DN, helped us to understand the potential effective dietary management strategies for the prevention and treatment of DN in a more comprehensive way from multiple dimensions, provided a theoretical basis for the development of more clinically effective prevention and control measures for DN, and provided directions for further clinical research.
The present umbrella review extracted 9 unique dietary interventions (including probiotics, a salt restriction diet, vitamin D, soy isoflavone, CoQ10, ketoanalog, dietary polyphenols, antioxidant vitamins, and low-protein diets) and 55 corresponding outcomes in meta-analyses, including 34 significantly associated outcomes and 21 nonsignificantly associated outcomes.All outcomes were classified as IV or NS (nonsignificant), and only five dietary interventions were rated as moderate-quality evidence.
First, compared with conventional care without probiotics, probiotic intervention significantly improved LDL-C (moderatequality evidence), TC (moderate-quality evidence), BUN (moderate-quality evidence), Scr (low-quality evidence), UACR (low-quality evidence), FBG (low-quality evidence), HbA1c (lowquality evidence), and HDL-C (low-quality evidence) in DN patients.He et al. (63) reported that probiotic supplementation can reduce the abundance of conditioned pathogenic bacteria, increase the abundance of beneficial intestinal bacteria, and reduce the release of enterogenic endotoxin, thus effectively improving blood sugar and blood lipid levels and kidney function.In recent years, an increasing number of studies have shown that inflammatory factors play a certain role in the pathogenesis of DN.Inflammation in DN patients is characterized by increased expression of inflammatory factors, inflammatory chemokines and adhesion factors; inflammatory cell infiltration; and increased CRP levels.Compared with that of classical inflammation, the severity of DN is mild, and DN is associated with a state of microinflammation (64).Firouzi et al. (65) showed that probiotic supplementation could reduce the content of enteric-borne urotoxins (such as para-cresol and indoxyl sulfate) in the blood of DN patients, inhibit the microinflammatory state of the whole body, and delay the deterioration of renal function.Proteinuria and changes in glomerular filtration membrane permeability in DN patients are closely related to vascular endothelial injury caused by oxidative stress, and DN patients often exhibit damage to the antioxidant defense system and an increase in free radical products.Probiotics can exert antioxidant effects through their own antioxidant system, such as regulating signaling pathways to produce various metabolites with antioxidant activity, such as glutathione (66).
Second, we found that compared with the usual or high-salt diet, the salt restriction diet significantly improved SBP (very lowquality evidence), DBP (very low-quality evidence), CrCl (lowquality evidence), and body weight (very low-quality evidence) in DN patients.High salt intake leads to elevated blood pressure caused by high sodium intake, which increases the risk of cardiovascular events in patients with DN.People with DN can lower their blood pressure by restricting salt, and in both type 1 and type 2 diabetes, salt restriction lasting 1 week leads to lower blood pressure (7.11/3.13mmHg in type 1 diabetes patients and 6.90/2.87mmHg in type 2 diabetes patients) (67).Current nutritional guidelines for patients with DN consistently recommend limiting dietary sodium intake to < 1.5 to 2.3 g/d (5 g NaCl).However, too low of a sodium intake may reduce insulin sensitivity and is not conducive to glucose homeostasis (68).
Third, the present umbrella re view showed that supplementation with soy isoflavones significantly improved BUN (low-quality evidence), FBG (low-quality evidence), total cholesterol (TC) (low-quality evidence), LDL-C (low-quality evidence) and 24-hour urine protein (very low-quality evidence) in DN patients compared with no supplementation with soy isoflavones.Studies have shown that soy foods can regulate blood lipid metabolism in the body to reduce low-density lipoprotein levels and increase high-density lipoprotein levels.Moreover, plant sterols contained in soybeans can competitively inhibit the body's cholesterol synthesis and reduce serum cholesterol levels (69).To improve kidney function, soy foods can reduce 24-h urinary protein levels.Replacing animal protein with a portion of soy protein in the diet does not adversely affect kidney function but also improves kidney hemodynamic function and reduces the elimination of urinary protein (5).Soybean protein itself is a high-quality protein and has a relatively high raw price.After the digestibility of soybean food is significantly improved, soybean protein and animal protein play the same nutritional role.Moreover, soy protein is lower in fat than animal protein is, which helps people with diabetes control the total calories in their diet and reduce the intake of too much fat, especially saturated fat, due to the consumption of human animal protein (69).More importantly, the unique nutrients of soy protein contribute to the stability of blood sugar and blood lipids in diabetic patients and can also remove excess free radicals in diabetic patients, reduce oxidative stress in the body, reduce the attack of glycoylation end products on the body's target organs, and prevent complications (70).
However, the effect of a low-protein diet on DN has been controversial.The basic principle of low-protein diet therapy is to reverse glomerular filtration and reduce uremic symptoms.Studies on patients with chronic kidney disease and advanced DN have shown that a low-protein diet can lead to malnutrition, which is a risk factor for mortality from this disease (71).Therefore, the beneficial effect of a low-protein diet on renal prognosis may be offset by the malnutrition of the treatment itself, and more importantly, a low-protein diet may increase the mortality of DN patients (72).The results of this study showed that a low-protein diet was not significantly associated with improved kidney function in patients with DN.Although these results do not completely negate other potential benefits of a low-protein diet for DN patients, the benefits of a low-protein diet on renal function are not significant (71).Urinary tract infection is also one of the common complications in patients with DN (73,74).However, the existing studies have not reported a significantly effective dietary intervention that can reduce the risk of urinary tract infection in patients with DN.The study by Chen et al. (73) found that vegetarianism was a protective factor for urinary tract infections, but the protective effect was not significant in the subgroup of patients with diabetes.In addition, Zaragoza-Marti et al. (75) believe that the Mediterranean diet can significantly reduce the risk of gestational diabetes and urinary tract infections, but there are no data on the effect of the Mediterranean diet on the development of urinary tract infections in diabetic patients.In addition, this study revealed that nutritional supplements such as CoQ10, dietary polyphenols and ketoanalog can effectively improve the clinical outcomes of DN patients, but the quality of evidence is low.

Limitations and strengths
This study has several limitations.First, we searched only English language databases, and studies in other languages were excluded, which may lead to potential bias.Second, only published data were extracted, and unpublished or forthcoming evidencebased evidence was ignored.Third, this study directly extracted and analyzed existing data from systematic reviews and meta-analyses, and data from those original studies not included in systematic reviews and meta-analyses were not included.Despite these acknowledged limitations, this umbrella review provides the first comprehensive documentation of the existing evidence from prior meta-analyses on the effects of dietary intervention on DN.This umbrella review evaluated the advantages and disadvantages of existing evidence-based medicine through a systematic review and meta-analyses of the effects of dietary intervention on DN.This review helps to elucidate potential dietary management strategies for the prevention and treatment of DN in a more comprehensive way from multiple dimensions, provides a theoretical basis for the development of more clinically effective prevention and control measures for DN, and provides directions for further clinical research.This study employed rigorous systematic methodologies.Two independent authors conducted the literature searches, selected the studies, and extracted the data.When sufficient data were available, we reanalyzed the RR, WMD, or SMD using 95% CIs with random or fixed effects models.We thoroughly assessed heterogeneity and publication bias for the inclusion of each metaanalysis.Additionally, we utilized three established approaches, namely, the AMSTAR, GRADE and evidence classification criteria, to appraise the methodological quality and evidence classification of each risk factor.This comprehensive evaluation enabled us to assess our confidence in the provided estimates.

Conclusion
The present umbrella review extracted 9 unique dietary interventions and 55 corresponding outcomes in meta-analyses, including 34 significantly associated outcomes and 21 nonsignificantly associated outcomes.All outcomes were classified as IV or NS (nonsignificant), and only five dietary interventions were rated as moderate-quality evidence.The results of this umbrella review showed that dietary interventions such as probiotics, a salt restriction diet, vitamin D, soy isoflavone, CoQ10, ketoanalog, dietary polyphenols, antioxidant vitamins, and low-protein diets could effectively delay the development of DN to some extent.The findings in this paper can aid in the development of better prevention and treatment measures to reduce the incidence of DN, delay its progression, and reduce the burden of DN-related disease worldwide.

TABLE 1
Evidence categories criteria.

TABLE 2
Effects of dietary intervention on diabetic nephropathy.aslow-qualityevidence,and17were rated as very low-quality evidence (Table2).Moderate-quality evidence and low-quality evidence for dietary interventions that could significantly improve clinical outcomes in patients with DN are presented in Figure2.
total of 4 meta-analyses (4, 22, 24, 28) studied the effect of vitamin D supplementation on DN incidence.The meta-analysis ofHe et al. published in 2022 ( A